Pharmaceutical methods using a substituted 10-aminoalkyl-9,10-dihydroanthracene

ABSTRACT

Pharmaceutical compositions comprising a substituted 10aminoalkyl-9,10-dihydroanthracene have utility as tranquilizers and/or antidepressants.

United States Patent 91 Craig et a1.

[ Mar. 26, 1974 PHARMACEUTICAL METHODS USING A SUBSTITUTEDl0-AMINOALKYL-9,l0- DII-IYDROANTHRACENE Inventors: Paul N. Craig,Ambler; Charles L.

Zirkle, Berwyn, both of Pa.

Assignee: Smithkline Corporation,

Philadelphia, Pa.

Filed: May 10, 1971 Appl. No.: 122,099

Related US. Application Data US. Cl. 424/330 Int. Cl A6lk 21/00 Field ofSearch 424/330 References Cited UNITED STATES PATENTS 2,403,483 7/1946Cusie 260/5708 2,520,153 8/1950 Lawson et al.. 260/294 3,192,204 6/1965Craig et a1. 260/240 3,403,157 9/1968 Humber et al 260/5708 X FOREIGNPATENTS OR APPLICATIONS 223,611 10/1962 Austria 260/5708 95,936 5/1963Denmark.... 260/5708 95,991 5/1963 Denmark 260/5708 646,048 11/1950Great Britain 260/5708 1,013,901 12/1965 Great Britain 260/5708 PrimaryExaminer-Stanley .1. Friedman Attorney, Agent, or Firm-Richard D.Foggio; William H. Edgerton [57] ABSTRACT Pharmaceutical compositionscomprising a substituted l0-aminoalkyl-9,IO-dihydroanthracene haveutility as tranquilizers and/or antidepressants.

10 Claims, No Drawings PHARMACEUTICAL METHODS USING A SUBSTITUTEDl-AMINOALKYL-9,IO-DII-IYDROANTHRACENE This application is a division ofapplication Ser. No. 742,171 filed on July 3, 1968, now US. Pat. No.3,622,630 which in turn is a continuation-in-part of application Ser.No. 631,584 filed Apr. 18, 1967, now abandoned, which is acontinuation-in-part of application Ser. No. 526,975 filed Feb. 14,1966,and now abandoned.

This invention relates to novel substituted l0-aminoalkyl-9,IO-dihydroanthracenes which have useful pharmacodynamicproperties. More specifically the novel products of this inventioneffect the central nervous system and have utility as tranquilizers. Thetranquilizing activity is demonstrated in standard pharmacological testprocedures employed in characterizing chlorpromazine and trifluoperazineat oral dosages in rats, mice and monkeys approximately equivalent tothe latter agents.

The novel 10-aminoalkyl-9, l O-dihydroanthracenes of this invention arerepresented by the following general structural formula:

FORMULAI when:

R represents hydrogen, lower alkyl, such as methyl or ethyl, or phenyl;

Y represents halogen having an atomic weight of less than 80, preferablychlorine, lower alkyl such as methyl, trifluoromethyl, lower alkylthiosuch as methylthio, lower alkylsulfonyl such as methylsulfonyl orN,N-dimethylsulfamyl;

A represents an alkylene chain, straight or branched,

( JHI (I) HCI-Ir- Z FORMULA II when:

R and R represent hydrogen or methyl; and

. dihydroanthracene Z represents monomethylamino, dimethylamino, N-piperidinyl, N-methyl-N-piperazinyl, N'-(whydroxyethyl)-N-piperazinyl,N-(w-acetoxyethyl)- N-piperazinyl.

Particularly advantageous compounds are lO-(3- dimethylaminopropyl)-2-trifluoromethyl-9, l 0- and 9-methyll 0-( 3- dimethylaminopropyl)-2-trifluoromethyl-9,l O- dihydroanthracene.

Compounds of formulas l and II above wherein R is lower alkyl or phenyl,in addition to having tranquilizing activity, also have utility asantidepressants. The anti-depressant activity is demonstrated instandard pharmacological test procedures employed in characterizingimipramine and amitryptyline at oral dosages in mice and ratsapproximately equivalent to the latter agents.

By the terms lower alkyl or alkoxy where used herein alone or incombination with other terms, groups having from 1 to 4, preferably 1 to2 carbon atoms are indicated.

This invention also includes stable, pharmaceutically acceptable,'acidaddition salts of the above defined bases formed with nontoxic organicand inorganic acids. Such salts are easily prepared by methods known inthe art. The base is reacted with either the calculated amount oforganic or inorganic acid in aqueous miscible, solvent such as acetoneor ethanol, with isolation of the salt by concentration and cooling oran excess of the acid in aqueous immiscible solvent, such as ethyl etheror chloroform, with the desired salt separating directly. Exemplary ofsuch organic salts are those with maleic, fumaric, benzoic, ascorbic,pamoic, succinic, bismethylenesalicylic, methane-sulfonic,ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric,gluconic, lactic, malic, mandelic, cinnamic, citraconic, as-

partic, stearic, palmitic, itaconic, glycolic, paminobenzoic, glutamic,benzene sulfonic and theophylline acetic acids as well as with the 8-chlorotheophylline and 8-bromotheophylline. Exemplary of such inorganicsalts are those with hydrochloric, hydrobromic, sulfuric, sulfamic,phosphoric, and nitric acids. These salts may also be prepared by theclassical method of double decomposition of appropriate salts which iswell known to the art.

The lO-aminoalkyl-9,IO-dihydroanthracenes of this invention are preparedby one of several routes depending on the nuclear (Y) substituent andthe presence of a 9-alkyl or phenyl group. When the 9-position isunsubstituted (R=l-l) the products are obtained advantageously via thefully aromatic anthracenes which are prepared as shown in the followingsynthetic scheme illustrated by way of example for Z represented bydimethylaminof FORMULA III in which Y and A are as defined in Formula Iand X is halogen, preferably chlorine.

According to the above procedure, the substituted anthrone is reactedwith a methoxyalkyl magnesium halide to give thelO-methoxyalkyl-l-hydroxy-9,l0- dihydroanthracenes. Advantageously thereaction is carried out in an inert organic solvent such as an ether,for example diethyl ether, dioxane or, preferably, tetrahydrofuran at atemperature of from about 0C. to room or ambient temperature for aperiod of about 3 to 24 hours. Removal of the solvent and treatment ofthe residue with water and/or an ammonium salt solution separates thelO-methoxyalkyl derivative. The latter is treated with concentrated(48%) hydrobromic acid to give simultaneous dehydration of the hydroxygroup and cleavage of the methyl ether linkage. The resultinglO-bromoalkyl-anthracenes are treated with a di-loweralkylamine as shownabove or ammonia, a mono-loweralkylamine, pyrrolidine, piperidine,N-lower alkyl-piperazine or N-(w-acetoxy-lower alkyl)-piperazine to givethe corresponding 10- aminoalkyl-anthracenes of Formula [11. The latteruseful intermediates are reduced to give the 9,10- dihydroanthraceneproducts of this invention with phosphorus and hydrogen iodide or withhydrogen ane copper chromite catalyst when Y is trifluoromethyl.

Hydrolysis of the N'-acetoxyalkylN-piperazinyl products thus formed withfor example sodium hydroxide solution yields the correspondingN-(w-hydroxylower alkyl)-N-piperazinyl derivatives of Formula 1. Furtheralkylation of the N-piperazinyl compounds thus obtained with an alkyleneoxide or alkylene halohydrin yields other N-substituted piperazinylcompounds of Formula I.

The 9-unsubstituted anthrone starting materials used as above are eitherknown or prepared conveniently as illustrated by the following outlineof the preparation of 2-trifluoromethyl-lO-anthrone. Phenyl magnesiumbromide is reacted with 2-bromo-4-trifluoromethylbenzonitrile to give2-bromo4-trifluor0methylbenzophenone. The latter is reduced with forexample phosphorus and hydrogen iodide to yield2-bromo-4-trifluoromethyl-diphenylmethane, which is reacted first withmagnesium, then with carbon dioxide to give 2-benzyl-Strifluoromethylbenzoic acid. Cyclization by acid treatment withfor example concentrated sulfuric acid furnishes the2-trifluoromethyl-lO-anthrone.

The compounds of Formula I when R is lower alkyl or phenyl andespecially when Y is trifluoromethyl are prepared as shown in thefollowing sequence illustrated by way of example for R is methyl and Zis dimethylamino:

lHBr

According to the above procedure, the substitutedZ-(a-methylbenzyl)-benzonitrile is reacted with a methoxy-alkylmagnesium halide as described more fully hereinabove to give themethoxyalkyl imine derivative. The latter is treated with concentrated(48%) hydrobromic acid to simultaneously ring close and cleave themethyl ether linkage. The resulting lO-bromoalkylanthracene is treatedwith the appropriate amine to give the correspondinglO-aminoalkyl-anthracene which is reduced with, preferably, hydrogen andcopto the 9-alkyl-9, l 0- 7 strong alkali such as an alkali metalhydride, i.e. sodium or potassium hydride or an alkali metal loweralkoxide such as sodium methylate or ethylate to givel-phenyll-(Z-bromo-4-trifluoromethylphenyl)-ethylene oxide. The latteris reduced with a bimetallic hydride such as lithium aluminum hydride ina suitable nonpolar organic solvent such as ethyl ether ortetrahyclrofuran to a-phenyl-a-(2-bromo-4-trifluoromethylphenyl)-ethanol. This alcohol is then reduced with phosphorus and hydrogeniodide to Z-(a-methylbenzyD-S- trifluoromethyl-bromobenzene which istreated with cuprous cyanide to give the corresonding benzonitrile.Alternatively, this benzonitrile may be hydrolyzed to the benzoic acidand cyclized with for example sulfuric acid to give9methyl-2-trifluoromethyl-10-anthrone which may be converted to productsof this invention as described hereinabove.

Either of the two general procedures described above for the preparationof compounds of Formula I may be interchanged. For example,2-bromo-4-trifluoromethyl-diphenylmethane is converted with cuprouscyanide to the 2-benzyl-5-trifluoromethylbenzonitrile which is thenreacted with a methoxyalkyl magnesium halide to give the imine followedby similar reactions as described above to furnish the corresponding 9-unsubstituted-9, 1 O-dihydroanthracene products.

Some of the compounds of this invention may be present as cis or transisomers as well as mixtures of these isomers. For example, when R informula I is other than hydrogen the geometrical isomers may berepresented as follows:

I A-Z H A-Z crs TRANS The isomers are separated by fractionalcrystallization of their acid addition salts from a suitable solvent ormixture of solvents such as, for example, acetone-ether orethanol-ether. Also, a pure isomer may be obtained directly from thereduction of the lO-aminoalkyl anthracene.

In addition, it will be readilyapparent to one skilled in the art thatcertain compounds of this invention may be present as optical isomers.These isomers are separated by recrystallization of the optically activeacid addition salts, for example the d-and l-di-ptoluoyltartrates of theracemic free base. Alternatively, a precursor in the synthesis of theproducts of formula I may be resolved into d-and l-isomers and theseparated isomers reacted further to give the optically active products.

The connotation of the general formulas presented herein is to includeall isomers, the separated d or 1 optical isomers as well as the dlmixture and the separated cis or trans isomers as well as the mixture ofthese isomers.

A useful pharmacological indicator of tranquilizing activity is theproduction of ptosis in rats. In thisprocedure rats'are examined afteroral administration of a test compound at hourly intervals for a ptoticeffect and the incidence of ptosis is recorded as a percentage of thenumber of test animals. Another test procedure for evaluatingtranquilizing activity is the suppression of rage in mice. A testcompound is administered orally to mice preselected for their ability toexhibit rage episodes during footshock and the animals are tested again.The percentage of animals exhibiting protection against rage isrecorded.

Antidepressant activity is measured pharmacologically by the ability ofa compound to prevent reserpine-induced ptosis in rats or mice. In thisprocedure a test compound is administered orally to the animals followedat various time intervals by 1 mg/kg of reserpine (i.v.) and the testanimals are observed 45 minutes thereafter for ptosis prevention.

The following table 1 sets forth comparative data obtained by employingthe above described test procedures for selected compounds of thisinvention and the closest known prior art l-aminoalkyl-9,l0-dihydroanthracenes.

TABLE 1 Rat ptosis, maximum Oral dose Percent Percent I (mg./kg.producpreven- Compound free base) tion tion l (CH2)a-N(CH3)2 CH3 CH3 4445.4

(H2)aN (CHa)2 Austria 223,611

D. Cis isomer:

H CH3 From' the above table it is observed that the prior art compoundsA and B are either inactive or demonstrate activity at dosesconsiderably higher than compounds C and D of the invention.

In general the separated l-isomer of a racemic compound of thisinvention is more active. pharmacologically than the correspondingracemic mixture as illustrated in table 2 for tranquilizing activity.

As noted hereinabove the compounds of formulas I and II wherein R islower alkyl or phenyl have both tranquilizing and antidepressantactivity. Thus the compound D in table 1 has an ED of 14.5 mg/kg in therat ptosis prevention test (antidepressant activity) and the samecompound B (dl-isomer) in table 2 has an ED of 32.1 mg/kg in the mouserage suppression test (tranquilizng activity). To demonstrate thatcompounds of formulas I and II when R is hydrogen do not haveantidepressant activity, test results are shown in table 3 for mouseptosis prevention.

Thus, although the parent compound A shown in table 3 has noantidepressant activity, the presence of a 9- methyl substituent incompound B incorporates a component of antidepressant activity whileretaining the already present tranquilizing activity of the parentcompound A. I

A further aspect of this invention relates to 9-substitutedlOaminoalkyl-9 l O-dihydroanthracenes which are not benzoring substituted. These compounds have anti-depressant activity with notranquilizing activity. The antidepressant activity is demonstrated instandard pharmacological test procedures employed in characterizingimipramine and amitryptyline at oral dosages in 'mice and ratsapproximately equivalent to the latter agents. These 9-substituted-l0-aminoalkyl-9,lo dihydroanthracenes are represented by the followinggeneral structural formula:

FORMULA IV when:

R represents lower alkyl, such as methyl or ethyl, or

phenyl; and

A and Z are as defined in formula I above.

The compounds of the formula IV are prepared advantageously by directalkylation of an R -substituted- 9,10-dihydroanthracene with a tertiaryaminoalkyl halide, such as dimethylaminopropyl chloride, in an inertorganic solvent, for example dimethylsulfoxide or an ether. Preferablyan alkali metal salt of the 9,10-

v 8 dihydroanthracene is employed which is prepared for example fromsodium hydride or butyl lithium. Alternatively, methods analogous tothose described for the preparation of compounds of formula I above maybe employed to obtain compounds of formula IV. Similarly these compoundsmay be present as cis, trans isomers which are separated byfractionation. Also, a pure cis isomer upon treatment with sodiumhydride in dimethylsulfoxide gives a mixture of cis, trans isomers fromwhich the pure trans isomer is separated.

In contrast to the compounds of formulas I and II wherein R is loweralkyl or phenyl which have both tranquilizing and antidepressantactivity, the compounds of formula IV which share the structural featureof 9-substituent but lack the benzo ring substituent have antidepressantactivity but no tranquilizing activity. This is shown in the followingtable 4.

TABLE 4 Rat ptosis, maximum Oral dose Percent Percent (mg/kg.producpreven- Compound free base) tion tion A. Cis isomer:

H CH3 88.5 0 22. 1

H (CH2)3 N(CH3)2 The novel compounds of this invention may beadministered orally or parenterally in conventional dosage unit formssuch as tablets, capsules, injectables or the like, by incorporating theappropriate dose of a compound offormula I or IV with carriers accordingto accepted pharmaceutical practices. In practice, unit doses of from 10mg. to 250 mg. administered from one to four times a day are effective.

The following examples are not limiting but are illustrative ofcompounds of this invention and procedures for their preparation andwill serve to make fully apparent all ofthe compounds embraced by thegeneral formu las given above. Alternatives and modifications of thegeneral procedures set forth herein will be apparent to those skilled inthe art.

EXAMPLE 1 A mixture of 12.7 g. of magnesium and 56.7 g. of 3-methoxypropyl chloride in 300 ml. of ether is refluxed for 1 hour. Theresulting mixture is cooled to about 10C. and a suspension of 34.3 g. of2-chlorol0- anthrone in 250 ml. of ether is added. The reaction mixtureis allowed to warm to room temperature and stand overnight. Most of theether is removed and the residue decomposed with ammonium sulfate in aminimum of water plus ice. The mixture is extracted with ether, theextract evaporated and the residue taken up into benzene. The benzene isextracted with alkali and then evaporated to give2-chloro-10-hydroxy-10-(3- methoxypropyl)-9, l O-dihydroanthracene.

A solution of 28.7 g. of the above 9,10-dihydroanthracene in 1 10 ml. of48 percent hydrobromic acid and 225 ml. of glacial acetic acid isrefluxed for 6 hours. The reaction mixture is then concentrated, dilutedwith water and made strongly alkaline. The solution is extracted withether and the dried extract is chromatographed on alumina to give2-chloro-l0-(3- bromopropyl)-anthracene, m.p. 7778C.

Into a solution of 10.0 g. of the above anthracene in 30 ml. of benzeneis bubbled about 12 g. of dimethylamine at room temperature. Theresulting mixture is heated in a pressure bottle on a steam bath forfour hours, cooled and allowed to stand. The reaction mixture is madebasic, treated with ether and filtered. The separated, dried ethersolution is evaporated to give 2-chloro-10-(3-dimethylaminopropyl)-anthracene; hydrochloride salt, m.p.234235C.

A mixture of 2.0 g. of the above free base and 2.0 g. of red phosphorusin 10 ml. of 57 percent hydroiodic acid is refluxed for 24 hours. Thereaction mixture is diluted with water, filtered, made basic andextracted with ether to give2-chloro-1(3-dimethylaminopropyl)-9,lO-dihydroanthracene; hydrochloridesalt, m.p. 20l203C.

EXAMPLE 2 A mixture of 18.2 g. of 2-chloro-l0-(3bromopropyl)- anthracene(prepared as in Example 1) and 11.0 g. of N-methyl-piperazine in 50 ml.of toluene is refluxed for 24 hours. The reaction mixture is made basicand extracted with ether to give 2-chloro-10-[3 (N'-methyl-N-piperazinyl)-propyl]-anthracene; hydrochloride salt, mp. 260C. dec.

A mixture of 2.0 g. of the above free base and 2.0 g. of red phosphorusin 10 ml. of 57 percent hydroiodic acid is refluxed for 24'hours. Thereaction mixture is diluted, filtered and made basic to give2-chloro-l0-[3- (N'-methyl-N-piperazinyl)-propyl]-9,10-dihydroanthracene; hydrochloride salt, mp. 233C. dec.

Similarly, by employing an equivalent amount of dibutylamine instead ofN-methylpiperazine in the above sequence, there is obtained2-chloro-10-(3- dibutylaminopropyl )-9, l O-dihydroanthracene.

EXAMPLE 3 To a solution of 20 g. of2-bromo-4-trifluoromethylbenzonitrile in 300 ml. of ether is added 29ml. ofa 3M solution of phenylmagnesium bromide in 100 ml. of ether andthe resulting mixture is refluxed for 3 hours, then stirred for 16 hoursat room temperature. The dried ether solution is evaporated and theresidue treated with excess dilute hydrochloric acid to give the iminewhich is heated on the steam bath for 1 hour. This mixture is extractedwith ether to give after fractional distillation,2bromo-4-trifluoromethylbenzophenone, m.p. 5253C.

A mixture of 12.5 g. of the above benzophenone and 12.5 g. of redphosphorus in 25 ml. of 57 percent by droiodic acid is refluxed andstirred under nitrogen for 24 hours. The reaction mixture is dilutedwith water, filtered and solid washed with ether and water. The ethersolution is dried and evaporated to give 2-bromo-4-tribluoromethyl-diphenylmethane, b.p. 97100 C./0.2 mm.

The Grignard reagent prepared from 5.0 g. of the above diphenylmethaneand 0.4 g. of magnesium in 50 ml. of tetrahydrofuran is poured into 200ml. of ether saturated with carbon dioxide at 80C. The reaction mixtureis extracted with dilute sodium hydroxide solution, neutralized withdilute acid and concentrated. The residue is taken up in ether, washedwith dilute hydrochloric acid, dried and concentrated to give 2-benzyl-5trifluoromethylbenzoic acid. m.p. 148l50 C.

A solution of 19.9 g. of the above acid in 58 ml. of concentratedsulfuric acid is stirred at room temperature for 3 hours, poured into700 ml. of water and filtered to give 2-trifluoromethyl-10-anthrone,m.p. l48l50C.

A mixture of 8.65 g. of 3-methoxypropyl chloride and 1.9 g. of magnesiumin ml. of ether is stirred and refluxed for 2 hours. To this mixture at10C. is added a suspension of 6.0 g. of 2-trifluoromethyl-l0- anthronein ether. After stirring for three hours at 10C., then 16 hours at roomtemperature, the reaction mixture is poured into ammonium chloridesolution and extracted with ether. The extract is evaporated, taken upin benzene, extracted with base, washed with water, dried and evaporatedto give 2-trifluoromethyll0-hydroxy- 1 0-( 3-methoxypropyl)-9, 1 0-dihydroanthracene. The latter, 2.0 g., in 7.5 ml. of 48 percenthydrobromic acid and 14 ml. of glacial acetic acid is refluxed for 6hours. The reaction mixture is evaporated, taken into ether andchromatographed to give Z-trifluoromethyl- 10-(3-bromopropyl)-anthracene, m.p. 8788C.

The above anthracene (15.0 g.) and 18 g. of dimethylamine in 45 ml. ofbenzene is heated on the steam bath in a pressure bottle for 6 hours.The reaction mixture is treated with water and extracted with dilutehydrochloric acid. The acid extract is made basic, extracted with etherand the dried ether extract is evapo rated to give2-trifluoromethyl-l0-(3-dimethylaminopropyl)-anthracene, b.p. 160C./0.35mm.

A mixture of 3.8 g. of the above anthracene, 0.6 g.

of copper chromite and 15 ml. of decalin is heated at 200C. under 4,000lbs. hydrogen pressure for three hours to give upon workup, the product2- trifluoromethyl-10-(3-dimethylaminopropyl)-9,l0- dihydroanthracene;hydrochloride salt, m.p. l94.51- 96C.

EXAMPL To a mixture of 0.72 g. of sodium hydride (56 percent suspensionin mineral oil) and 3.7 g. of tri'methylsulfoxonium iodide in 25 m1. ofdimethylsulfoxide is added 5.0 g. of2bromo-4-trifluoromethylbenzophenone (prepared asin Example 3) in 8 ml.of dimethylsulfoxide. The resulting mixture is stirred for 30 minutes atroom temperature then heated at 5055C. for 90 minutes. The reactionmixture is poured into water, extracted with ether, and the extractevaporated to give l-phenyl- 1 2-bromo-4-trifluoromethyl-phenyl ethyleneoxide, m.p. 7778C.

The above oxide (127- g.) in 55 ml. of ether is added to 1.0 g. oflithiumaluminum hydride in 55 ml. of ether and the mixture is refluxedfor 1 hour. Water (2 ml.) is added and the reaction mixture is filteredto give a-phenyl-a-(2bromo-4-trifluoromethylphenyl)-ethanol. The latter(12.5 g.) is refluxed and stirred with 12.5 g. of red phosphorus and 25ml. of 57 percent hydroiodic acid for 24 hours. The reaction mixture isfiltered to give 2-(a-methylbenzyD-Strifluoromethyl-bromobegging- Amixture of 2.4 g. of the above bromobenzene, 0.7- g. of cuprous cyanideand 1.5 ml. of dimethylformamide is stirred and refluxed for 4 hours.The reaction mixture is poured into a solution of 3.1 g. of ferricchloride in 4.5 m]. of water and 0.8 ml. of concentrated hydrochloricacid, extracted with chloroform, waterwashed, dried and distilled togive 2-(a-methylbenzyl)- 5-trifluoromethylbenzonitrile.

To the Grignard solution formed with 6.2 g. of 3- methoxypropyl chlorideand 1.4 g. of magnesium in 75 ml. of tetrahydrofuran is added 5.0 g. ofthe above nitrile in 50 ml. of tetrahydrofuran and the mixture isrefluxed for 2 hours. The reaction mixture is decomposed with ammoniumchloride solution and extracted with ether. The dried ether extract isevaporated to give the methoxypropyl imine (29 g.) which is refluxed for6 hours in 100 ml. of 48 percent hydrobromic acid and 200 ml. of aceticacid. The reaction mixture is evaporated, extracted with ether and thedried extract chromatographed to give 2-trif1uoromethyl-9-methyll0,(3-bromopropyl)-anthracene.

A mixture of 12.0 g. of the above anthracene and 18 g. of dimethylaminein 60 ml. of dry benzene is heated in a pressure bottle on a steam bathfor 5 hours. The

reaction mixture is treated with water and extracted with dilutehydrochloric acid. The acid extract is made basic, extracted with etherand the dried extract evaporated to give2-trifluoromethyl-9-methyl-10-(3-dimethylaminopropyl)-anthracene, b.p.l65-170C./0.l mm.; hydrochloride salt, mp. 263C. (dec.).

The above anthracene (2.0 g.) is reduced with 0.34 g. of copper chromitein 4 ml. of decalin at 200C. and 4,000 lbs. hydrogen for 3 hours to give2- trifluoromethyl-9-methyl-10-(3- dimethylaminopropyl)-9, 1O-dihydroanthracene; hydrochloride salt, m.p. l79l8 1C. This is thecisisomer.

Similarly, reaction of 2-trifluoromethyl-9-methyl-l0-(3-bromopropyl)-anthracene with N-methylpiperazine as described abovefollowed by reduction yields the corresponding 2-trifluoromethyl-9-methyl-l0 [3-(N'- methyl-N-piperazinyl ).-propyl]-9,ldihydroanthracene.

EXAMPLE A mixture of 12.0 g. of 2-trifluoromethyl-l0-(3-bromopropyl)-anthracene (prepared as in Example 3) and 4.9 g. ofN-methylpiperazine in 40 ml. of benzene is heated in a pressure bottleon the steam bath for 12 hours. Water is added to the reaction mixture,made basic and benzene separated which gives 2- trifluoromethyl--[3-(N'-methyl-N-piperazinyl)- propyl]-anthracene, b.p. l85-l89C./0.lmm.; hydrochloride salt, m.p. 280C. (dec.).

The above anthracene free base (4.6 g.) in 10 ml. of

. decalin and 0.74 g. of copper chromite are heated at 2- EXAMPLE 6Following the general procedures of Example 1, a mixture of 12.7 g. ofmagnesium and 64.0 g. of 3-methoxy-2-methylpropyl chloride in 300 ml. ofether is treated with 31.2 g. of 2-methyl-lO-anthrone in 250 m1. ofether to give 2-methyl-10-hydroxy-lO-(3- methoxy-2-methylpropyl )-9,lO-dihydroanthracene. The latter is similarly dehydrated and hydrolyzedwith 48 percent hydrobromic acid and the bromo compound reacted withdimethylamine to give 2-methyl- ]0-(3-dimethylamino-2-methylpropyl)-anthracene. Reduction with redphosphorus and 57 percent hydroiodic acid yields the product,2-methyl-l0-(3- dimethylamino-2-methylpropyl )-9, l 0-dihydroanthracene.

EXAMPLE 7 Following the procedure outlined in Example 3, 2-trifluoromethyll 0-( 3-bromopropyl )-anthracene 15.0 g.) is treated withexcess aqueous ammonia, methylamine or butylamine to give afterreduction the I products, 2-trifluoromethyl-10-(3-aminopropyl)-9,10-dihydroanthracene, 2-trifluoromethyl-l0-(3-methylaminopropyl)-9, 1O-dihydroanthracene andZ-trifluoromethyll0-(3-butylaminopropyl)-9,10-dihydroanthracene,respectively.

EXAMPLE 8 Hydrolysis of the above acetoxyethyl compound fur-- nishes2-trifluoromethyl-l0-[3-(N'-B-hydroxyethyl-N- piperazinyl)-propyl]-9,IO-dihydroanthracene.

Alkylation of the above hydroxyethyl compound with bromohydrin in thepresence of potassium carbonate yields2-trifluoromethyl-l0-[3-(N'-w-hydroxyethoxyethyl-N-piperazinyl)-propyl]-9 ,1 O-dihydroanthracene.

EXAMPLE 9 A mixture of 10 g. of 2-.trifluoromethyl-9-methyl-l0-(3-climethylaminopropyl)-anthracene (prepared as in Example 4), 15 g. ofred phosphorus and ml. of 57 percent hydroiodic acid solution isrefluxed and stirred for 40 minutes. The reaction mixture is poured intowater, made basic with sodium hydroxide solution, stirred for 1 hourwith excess ether and filtered. The dried filtrate is evaporated invacuo to give the free base which is a mixture consisting of aboutpercent of the transand 20 percent of the cis-isomer of2-trifluoromethyl-9- methyl- 1 0-( 3-dimethylaminopropyl)-9, l 0-dihydroanthracene. Recrystallization of the hydrochloride salt of themixture from acetone-ethyl acetate yi'elds the pure trans-isomerhydrochloride, m.p. 200-20 1C.

EXAMPLE 10 A mixture of 18.5 g. of l-di-p-toluoyltartaric acid and 16.7g. of cis-2-trifluoromethyl-9-methyl-10-(3- dimethylaminopropyl)-9,IO-dihydroanthracene (prepared as in Example 4) in ml. of boilingmethanol and 10 ml. of water yields the l-di-p-toluoyltartrate salt, mp.167C. (foam), [a] =+3.66. The free base liberated from this salt withammonium hydroxide and ether is converted to the hydrochloride salt ofd-cis-2- trifluoromethyl-9-methyll 0-( 3- dimethylaminopropyl)-9, 1O-dihydroanthracene, m.p. 209'210C., [011 +9.62 (2 percent ethanol).

The filtrate from the crude l-di-p-toluoyltartrate salt above is treatedwith ammonium hydroxide and ether to regenerate 13.5 g. of the cis freebase. The latter with 15.0 g. of d-di-p-toluoyltartaric acid in 200 ml.of methanol and m1. of water forms the d-di-ptoluoyltartrate salt,[01],, =2.4 (1 percent ethanol). The liberated free base is converted tothe hydrochloride salt of l-cis-2-trifluoromethyl-9methyl-10-(3-dimethylaminopropyl )-9, 1 O-dihydroanthracene, m.p. 206-208C., [0:]-9.6 (2 percent ethanol).

EXAMPLE 1 1 To a solution of 71.8 g. of2-benzyl-5-trifluoromethylbenzonitrile (prepared from 2-bromo-4-trifluoromethyldiphenylmethane by reaction with cuprous cyanide) in 100ml. of other is added gradually 183 ml. of 3M methyl magnesium bromidein ether. The reaction mixture is refluxed with stirring for six hours,decomposed with aqueous ammonium chloride, extracted with ether andevaporated. The residue is taken up in 250 ml. each of 48 percenthydrobromic acid solution and acetic acid, refluxed for 18 hours,evaporated and extracted with chloroform. The filtered extract isevaporated, the residue is dissolved in methanol and the solvent removedto give 2-trifluoromethyllO-methylanthracene, m.p. 98-100C.

A mixture of the above prepared anthracene (33.2 g.) and 34.2 g. ofN-bromosuccinimide in 300 ml. of carbon tetrachloride, catalyzed by 0.34g. of benzoyl peroxide, is refluxed and stirred for two hours. The hotreaction mixture is filtered and cooled to precipitate2-trifluoromethyll O-bromomethylanthracene.

To 5.2 g. of 57 percent sodium hydride in 100 ml. of dimethylsulfoxideat 50C. is added slowly a solution of 19.8 g. of diethylmalonate indimethylsulfoxide and the mixture is heated at 75C for 45 minutes. Aslurry of 36.5 g. of Z-trifluoromethyl-lO-brorndmethylanthracene indimethylsulfoxide is added and the resulting mixture is heated at 75Cfor 1 hour. The reaction mixture is quenched with water and extractedwith ether to give diethyl(3-trifluoromethyllO-anthracenylhmethylmalonate. The latter (50.7 g.) ishydrolyzed with 41 g. of potassium hydroxide in 200 ml. of 60 percentaqueous ethanol to the free malonic acid which is heated at l85200C. toobtain 2- trifluoromethylanthracene-10-propionic acid.

A mixture of 32.7 g. of the above prepared propionic acid and 48 g. ofred phosphorus in 160 m1. of 57 percent hydroiodic acid and 75 ml. ofacetic acid is refluxed and stirred for 3 hours. The reaction mixture isdiluted with water, extracted with chloroform, washed with water andevaporated to yield 2-trifluoromethyl-9,10-dihydroanthracene-l0-propionic acid, m.p. 153-155C.

A solution of 8.0 g. of 2-trifluoromethy1-9,l0- dihydroanthracene- 1O-propionic acid and 3.0 g. of d-aphenethylamine in 45 ml. of ethanol isclouded with 50 ml. of water while boiling to give the d-aphenethylaminesalt, m.p. 179-181C., [0:] 3.2 (1 percent ethanol). This salt isacidified with hydrochloric acid, extracted with ether and the driedextract evaporated to give l-2-trifluoromethyl-9,10-dihydroanthracene-l0-propionic acid. The latter is refluxed with 5 ml.of thionyl chloride for 2 hours and the resulting acid chloridedissolved in 20 ml. of benzene is saturated with dimethylamine to yieldthe dimethylamide. The amide (2.2 g.) in ether is added to 1.1 g. oflithium aluminum hydride in ether, refluxed for one hour and worked upto give d-2-trifluoromethyl- 10-( 3-dimethylaminopropyl )-9, 1O-dihydroanthracene; hydrochloride salt, m.p. 20l202C., [01], +4.92 (1percent ethanol).

The filtrate from the crude d-a-phenethylamine salt above is evaporated,acidified and extracted with ether to regenerate2-trifluoromethyl-9,10-dihydroanthracene-IO-propionic acid. The latter(6.2 g.) and 2.4 g. of l-a-phenethylamine dissolved in 30 ml. of ethanolis clouded while boiling with ml. of water to give thel-a-phenethylamine salt, m.p. 177-179C., [M +3.46. This salt isacidified to liberate d-2- trifluoromethyl-9, lO-dihydroanthracenelO-propionic acid which is treated as above with thionyl chloride, theacid chloride reacted with dimethylamine and the amide reduced withlithium aluminum hydride to yieldl-2-trifluoromethyl-lO-(3-dimethylaminopropyl)-9,10- dihydroanthracene;hydrochloride salt, m.p. 200-202- C., [a] =5.73 (1 percent ethanol).

EXAMPLE 12 7 Following the general procedure of Example 3, 18.2 g. of2-bromo4-methylthiobenzonitrile (obtained from 4-methylthiobenzonitrile) and 29 ml. of 3M phenylmagnesium bromide inether solution are reacted to give 2-bromo-4-methylthiobenzophenone. Amixture of the latter and red phosphorus in 57 percent hydroiodic acidis refluxed and stirred under nitrogen for 24 hours to give2-bromo-4-methylthiodiphenylmethane. The Grignard reagent prepared fromthis diphenylmethane in tetrahydrofuran is poured into ether saturatedwith carbon dioxide at 80C. Workup yields 2-benzyl-5methylthiobenzoicacid. A solution of the acid in concentrated sulfuric acid is stirred atroom temperature to give the ring-closed product, 2- methylthio- 1O-anthrone.

To the Grignard reagent prepared from 8.65 g. of 3- methoxypropylchloride in ether is added a suspension of 5.5 g. of2-methylthio-l0-anthrone in ether. After stirring for three hours at10C. and 18 hours at room temperature, the reaction mixture isdecomposed and worked up to give 2-methylthio-l0-hydroxy-10-(3-methoxypropyl)-9,10-dihydroanthracene. The latter is refluxed in 48percent hydrobromic acid and glacial acetic acid to give2-methylthio-l0-(3-bromo-propyl)- anthracene.

The above anthracene (13.7 g.) and 18 g. of dimethylamine in benzene isheated on the steam bath in a pressure bottle for 6 hours to give uponworkup 2- methylthio- 1 0-( 3-dimethylaminopropyl )-anthracene which ishydrogenated in the presence of copper chromite to yield2-methylthio-10-(3-dimethylaminopropyl)-9,10-dihydroanthracene.

EXAMPLE 13 Following the general procedure of Example 3, 16.8 g. of3-bromo-4-cyano-N,Ndimethylbenzenesulfonamide (obtained from4-cyano-N,N-dimethylbenzenesulfonamide) in ether is reacted with 29 ml.of 3M phenylmagnesium bromide in ether and the mixture worked up to give2-bromo-4-(N,N-dimethylsulfamyl)- benzophenone which is reduced with redphosphorus and hydroiodic acid to the corresponding diphenylmethane. TheGrignard reagent prepared from this diphenylmethane is reacted withcarbon dioxide with cooling to give 2-benzyl-5-(N,N-dimethylsulfamyl)-benzoic acid. Ring closure is effected via concentrated sulfuric acid toyield 2-(N,N-dimethylsulfamyl)-l0- anthrone.

The Grignard reagent prepared from 8.65 g. of 3- methoxypropyl chlorideis reacted with 5.0 g. of the above-prepared anthrone to give 2-( N,N-dimethylsulfamyl 1 O-hydroxyl 3-methoxypropyl 9,10-dihydroanthracene.The latter is refluxed in 48 percent hydrobromic acid and glacial aceticacid to give 2-(N,N-dimethylsulfamyl)-10-(3-bromo-propyl)- anthracene.

The above anthracene (12.6 g.) and 18 g. of dimethylamine in benzene isheated on the steam bath in a pressure bottle for six hours to give uponworkup 2- (N,N-dimethylsulfamyl)--(3-dimethylaminopropyl)- anthracenewhich is hydrogenated in the presence of copper chromite to yield2-(N,N-dimethylsulfamyl)- 10-( 3-dimethylaminopropyl)-9, lO-dihydroanthracene.

EXAMPLE 14 To a solution of 32.9 g. of2-bromo-4-trifluoromethylbenzophenone in 400 ml. of ether is added oneequivalent of ethylmagnesium bromide in ether and the resulting mixtureis refluxed for 4 hours. Treatment with aqueous acid givesa-phenyl-oz-(2-bromo-4-trifluoromethylphenyl)-propanol. The latter (13.0g.) is refluxed and stirred with 12.5 g. of red phosphorus and 25 ml. of57 percent hydroiodic acid for 24 hours to yield2-(a-ethylbenzyl)-5-trifluoromethylbromobenzene.

A mixture of 2.5 g. of the above bromobenzene, 0.7 g. of cuprous cyanideand 1.5 ml. ofdimethylformamide is stirred and refluxed for 4 hours. Thereaction mixture is poured into a solution of 3.1 g. of feric chloridein 4.5 m1. of water and 0.8 ml. of concentrated hydrochloric acid,extracted with chloroform, waterwashed, dried and distilled to give2-(a-ethylbenzyl)-5- trifluoromethylbenzonitrile.

To the Grignard reagent formed with 6.2 g. of 3- methoxypropyl chloridein 75 ml. of tetrahydrofuran is added 5.2 g. of the above nitrile andthe mixture is refluxed for 2 hours. The decomposed reaction mixtureyields the methoxypropyl imine which is refluxed for six hours in 100ml. of 48 percent hydrobromic acid and 200 ml. of acetic acid. Thereaction mixture is evaporated, extracted with ether and the driedextract chromatographed to give 2-trifluoromethyl-9-ethyl-10-(3-bromopropyl )-anthracene.

A mixture of 12.5 g. of the above anthracene and 18 g. of dimethylaminein 60 ml. of dry benzene is heated in a pressure bottle on a steam bathfor five hours. The reaction mixture is heated with water and extractedwith dilute hydrochloric acid. The acid extract is made basic andfurther worked up to give 2-trifluoromethyl- 9-ethyll 0-(B-dimethylaminopropyl)-anthracene. The latter (2.8 g.) is reduced with0.34 g. of copper chromite in 4 ml. of decalin at 2009C. and 4,000 lbs.hydrogen to yield 2-trifluoromethyl-9-ethyl-10-(3-dimethylaminopropy1)-9, l O-dihydroanthracene.

Similarly by commencing the above sequence of reactions employingphenylmagnesium bromide instead of ethylmagnesium bromide there isobtained the corresponding 2-trifluoromethyl-9-phenyl-10-(3-dimethylaminopropyl)-9, 1 O-dihydroanthracene.

EXAMPLE 1 5 To a suspension of 2.1 g. of 56 percent sodium hydride in 45ml. of dimethylsulfoxide is added gradually, with stirring, 7.5 g. of9-methyl-9, l 0- dihydroanthracene and the mixture heated at C. for 2hours. A solution of 7.5 g. of 3-dimethylaminopropyl chloride in 30 m1.of dimethylsulfoxide is added ancl heating is continued for 3 hours. Thereaction mixture is quenched with water, extracted with ether and theether extracted with dilute hydrochloric acid. The acid extract is madebasic to give the liberated base, 9-methyl-10-(3-dimethylaminopropyl)-9,l0- dihydroanthracene; hydrochloridesalt, m.p. 213216- C.

EXAMPLE 16 To a solution of 24.8 g. of 9-methyl-9,l0- dihydroanthracenein 300 ml. of ether is added over 15 minutes 96 ml. of 15 percent butyllithium in hexane and the resultingmixture is stirred at roomtemperature for 2 hours. After adding 24.6 g g. of 3-dimethylaminopropyl chloride, the mixture is stirred and refluxed for.3hours and allowed to stand overnight. The reaction mixture is extractedwith dilute hydrochloric acid, made basic, extracted with ether anddistilled to give the free base, b.p. 160C./0.5 mm. The latter isfractionated and the first fraction collected at b.p. l39C./0.l5 mm. iscis-9-methyl-l0-(3- dimethylaminopropyl)-9, l O-dihydroanthracene;hydrochloride salt, m.p. 2l7-218C.

The second fraction obtained from above (4.5 g.) is heated about 1 hourat 70C. with 0.81 g. of 57 percent sodium hydride in 40 ml. ofdimethylsulfoxide. The reaction mixture is quenched in water, extractedwith ether, dried and evaporated. The residual free base is converted toa hexamate salt in acetone and recrystallized from acetonitrile to givetrans-9-methyl-10-(3- dimethylaminopropyl)-9, 1 O-dihydroanthracenehexamate, m.p. l69l71C.

What we claim is:

1. A method of producing antidepressant and/or tranquilizing activitywhich comprises administering orally or parenterally to an animal in anamount sufficient to produce said activity a chemical compound of thestructural formula:

6. The method of claim in which the compound is the l-isomer.

7. The method of claim 1 in which the active medicament is administeredin unit doses of from mg. to 250 mg. for from one to four times a day.

8. A method of producing antidepressant activity which comprisesadministering orally or parenterally to an animal in an amountsufficient to produce said activity a chemical compound of thestructural formula:

in which:

R is lower alkyl or phenyl;

A is an alkylene chain of 2 to 4 carbon atoms; and

Z is amino, mono-loweralkylamino or di-loweralkylamino;

each of said lower alkyl moieties having from 1 to 4 carbon atoms, orits nontoxic, pharmaceutically acceptable, acid addition salt.

9. The method of claim 8 in which R is methyl, A is propylene, Z isdimethylamino and the compound is the cis-isomer.

10. The method of claim 8 in which the active medicament is administeredin unit doses of from 10 mg. to

250 mg. for from one to four times a day.

2. The method of claim 1 in which R is hydrogen or methyl, Y is2-trifluoromethyl, A is propylene and Z is dimethylamino.
 3. The methodof producing tranquilizing activity in accordance with claim 2 in whichR is hydrogen.
 4. The method of claim 3 in which the compound is thel-isomer.
 5. The method of claim 2 in which R is methyl and the compoundis the cis-isomer.
 6. The method of claim 5 in which the compound is thel-isomer.
 7. The method of claim 1 in which the active medicament isadministered in unit doses of from 10 mg. to 250 mg. for from one tofour times a day.
 8. A method of producing antidepressant activity whichcomprises administering orally or parenterally to an animal in an amountsufficient to produce said activity a chemical compound of thestructural formula:
 9. The method of claim 8 in which R2 is methyl, A ispropylene, Z is dimethylamino and the compound is the cis-isomer. 10.The method of claim 8 in which the active medicament is administered inunit doses of from 10 mg. to 250 mg. for from one to four times a day.